Genetic architecture and adaptation of Ladakh highlanders of trans-Himalayas

Abstract

Trans-Himalayan Ladakh has witnessed complex cultural movements and demographic changes since the Neolithic period, which is still continue despite the harsh, inhospitable and cold climate. Although geographically isolated from mainland South Asia, Ladakh has historic trade routes and is well connected and accessible to travelers from Tibet and Central Asia. Despite its rich cultural heritage, a detailed description of the genetic landscape of the Ladakh region is completely lacking, particularly with regard to genome-wide analysis and larger sample sizes. Therefore, in the current study, we genotyped 80 individuals from Kargil and Leh districts of the Union Territory of Ladakh, India. Here, we performed a comprehensive genetic analysis based on allele frequency and haplotype sharing. Our analysis revealed the presence of two distinct genetic lineages in the region with quite distinct genetic composition. The population of Leh Region is more similar to East Asian and Southeast Asian populations. In contrast, the population of the Kargil Region (LDKLA) is more similar to Indo-European populations. Demographic modeling suggests that the Leh group shares a genetic history with Tibetans, while the Kargil group showed great affinities with Kashmiri Muslims, Gujjars and Nepalese Brahmins, and both showed recent admixture. Both groups have experienced a founder event around during 11th to 22nd generations ago, the duration of which coincided with the Mughal invasion. The genome-wide scan for a signal of positive selection revealed genetic signatures of high-altitude adaptation (EPAS1 and ELMO2) in the Leh population, while in the Kargil population the key gene signatures were associated with immunity and female fertility.